Elucidation of the molecular mechanisms involved in the epigenetic regulation of gene expression remains the 'holy grail'for many research fields in biology. Recently, we made the exciting discovery of the first bona fide histone demethylase. The identification of Lysine-Specific Demethylase 1(LSD1), an H3-lysine 4 (H3- K4) specific histone demethylase confirmed the long held speculation regarding the reversible nature of histone methylation, and represents a major advance in our understanding of epigenetic regulation. LSD1 functions as an FAD dependent transcriptional corepressor and is found in a variety of multi-subunit complexes. A detailed knowledge of the precise mechanisms underlying the activity and regulation of these chromatin modulating complexes and their components is an essential step toward the eventual understanding of the essence of both genome organization and genomic information processing. The focus of our research is on the regulation of histone demethylases and the biological consequences of histone demethylation in gene regulation and DNA repair, which are two of the most essential events during stem cell differentiation, embryonic development, and cancer progression. Furthermore, we intend to identify additional novel histone demethylases, including those that may either exhibit alternative substrate specificities and perhaps different chemical mechanisms. These data will contribute further to this quickly moving and groundbreaking field of epigenetics. The findings from the studies described here will provide specific insights into the mechanisms underlying histone demethylation and will expand our knowledge of general epigenetic regulation as it relates to nearly every facet of genome-related biology and rapidly emerging cancer epigenetics. This work will undoubtedly have significant impact on a variety of human pathologies, including tumorigenesis and developmental anomalies.